Introduction
Over the last 25 years, our collective knowledge of dry eye disease (DED) has grown exponentially, yet many of the most commonly used clinical diagnostic tests have remained largely the same. What has changed is how we, as clinicians, approach the clinical diagnostic process differently than what was done at the inception of the initial dry eye definition in 1995, published in the Report of the National Eye Institute/Industry workshop on Clinical Trials in Dry Eyes by Lemp et al. At the time, dry eye was largely considered a sign-only–based condition, primarily fluorescein corneal staining. Today, over 25 years later, dry eye screening algorithms begin with an assessment of a patient’s dry eye symptoms, including visual disturbances, with the understanding that dry eye symptoms do not always correlate with dry eye signs. In addition, unless a patient is specifically asked about current or episodic dry eye symptoms and associated factors, a diagnostic opportunity may be missed.
The Tear Film and Ocular Surface Society (TFOS) Dry Eye WorkShop (DEWS) II report (2017) defined DED as a multifactorial condition of the ocular surface characterized by a loss of homeostasis of the tear film, accompanied by dry eye symptoms, including visual disturbances. In addition to symptomatology, clinical diagnostic testing should mirror the definition, and assess parameters of tear film homeostasis and known etiologies: tear film instability, hyperosmolarity, ocular surface inflammation and damage, and neurosensory anomalies. This chapter will review available testing across these parameters with the caveat that there will be tests not covered here, but the general concepts and underlying principles will be reviewed. In addition, diagnostic instrumentation and concepts on the horizon with be presented, with a nod to the diagnostic and management future of ocular surface disease.
In the TFOS DEWS report (2007), dry eye testing was often described as two-tiered, whereby a shortened battery of tests could be performed in a general clinical setting, and more advanced procedures and instrumentation were recommended for use in specialty clinics or in research settings. Advances in technology have brought a number of diagnostic instruments and therapeutics to clinical practice in the last 10 to 15 years. In part because of this, specialty clinics solely dedicated to dry eye and ocular surface disease management are becoming more commonplace. However, this can contribute to the perception that DED is becoming more confusing, with more expensive instrumentation required to diagnose and manage the disease. A simplistic approach to screening for dry eye in routine eyecare, followed by an in-depth dry eye assessment when available, is a modern approach, the early detection, prevention, and management of DED. The dry eye screening diagnostic algorithm in the TFOS DEWS II Diagnostic Methodology report utilizes this approach, simplifying dry eye screening so that everyone in an eyecare setting can make an initial diagnosis, followed by additional testing to further classify dry eye subtype. Asking questions, examination with the slit lamp, and making follow-up diagnostic and management symptoms simplifies the process. Critical diagnostic tests are discussed below.
Symptoms
While inquiring about symptoms of dryness and discomfort is the first step in screening for dry eye, the absence of symptoms does not preclude dry eye. The dry eye classification scheme reported in the TFOS DEWS II Diagnosis and Classification report includes pathways to a dry eye diagnosis for asymptomatic or symptomatic patients. Asymptomatic patients can present with no signs of DED and, therefore, no a nondry eye (normal) diagnosis is made and no treatment is required. However, an asymptomatic patient can also present signs with DED, due to a neurotrophic ocular surface or lack of patient report (consider a patient in for a cataract evaluation, for example) and whereby a diagnosis is subsequently made and management is necessary, especially presurgical procedures and in neurotrophic conditions. Patients presenting with symptoms of DED can show signs on the ocular surface as well as showing no signs. Patients with no signs are usually in the preclinical state or have neuropathic pain (nonocular surface disease). Therefore, these patients would need to be carefully observed, offer education/preventative therapy as well as possible referral for pain management. Dry eye is multifactorial, thus every case is different and a practitioner should use both signs and symptoms to diagnose dry eye and be able to design a tailored management approach to fit the patient’s level of DED.
Ocular surface symptoms are important to recognize and are often underestimated by clinicians. Symptom screening can help practitioners identify DED. Currently, the presence of ocular symptoms and signs of DED are required to approve therapeutic products for dry eye, and are often evaluated simultaneously in the dry eye exam. There is not a linear relationship between the signs and symptoms of DED as it varies between individuals and types of DED and across disease severity. It is crucial to monitor the progression of DED and its response to treatments and, therefore, a validated symptom questionnaire at the beginning of every clinical assessment with the patient is recommended.
Symptomatic patients usually present with dry and gritty sensation on the ocular surface, often described as discomfort, and in more severe cases, as a burning/stinging feeling, foreign body sensation, excess tearing, achy/sore eyes and pain, redness, photophobia, and intermittent episodes of blurred vision. These symptoms can be aggravated in environmental conditions such as low humidity and air conditioning, and forced heat in the winter months.
Questionnaires
In clinical research symptoms are gathered by questionnaires which are most often completed by the patient without any input from clinicians. These questionnaires often measure ocular surface discomfort, DED-related visual symptoms, the impact of DED on health-related quality of life, and are also used in clinical care.
Ocular Surface Disease Index
Diagnosis of DED can be initiated by symptom questionnaires such as the Ocular Surface Disease Index (OSDI) which explores different aspects of dry eye symptoms including frequency, identification of precipitation factors, and impact on quality of life. The OSDI questionnaire contains three sections: the frequency of occurrence of several symptoms (e.g., gritty feeling in eye, light sensitivity, and blurred vision), questions indicating limitations on certain activities (reading, driving at night, watching television), and the effect of environmental conditions on ocular surface (wind, low humidity, and air conditioning). The questionnaire has established and validated cutpoints and clinically meaningful changes that have been reported in the literature, and the TFOS DEWS II Diagnostic Methodologies report recommends an OSDI score ≥13 as a positive screening for dry eye and a change of ≥7 indicative of a meaningful change. This is the most commonly utilized dry eye questionnaire (DEQ-5) in dry eye clinical trials.
Dry Eye Questionnaire
The DEQ-5 consists of five questions which are related to frequency and intensity of ocular symptoms. These include frequency of watery eyes, discomfort and dryness, and the noticeability of late day symptoms. The DEQ-5 (short form) has been validated and is also recommended for dry eye screening by the TFOS DEWS II Diagnostic methodology report with a positive dry eye screening score of ≥6.
Impact of Dry Eye on Everyday Living
The Impact of Dry Eye on Everyday Living questionnaire includes two types of visual disturbance queries which are by how much the patient is bothered by “blurry vision” or “sensitivity to light, glare, and/or wind.” It shows promise in that it assesses quality of life, but does not have widespread adoption.
National Eye Institute Visual Function Questionnaire
The National Eye Institute’s Visual Function Questionnaire is a generic visual function questionnaire which has seven visual sections including general vision, distance vision, peripheral vision, driving, near vision, color vision, and ocular pain. The pain subscale has been correlated positively to dry eye.
Speed Survey
The Standard Patient Evaluation of Eye Dryness Questionnaire (SPEED) questionnaire was designed to quickly track the progression of dry eye symptoms over time in DED and with contact lens wear. Drs. Korb and Blackie reported that this questionnaire gives a score from 0 to 28 that is the result of eight items that assess frequency and severity of symptoms. The survey is validated, and commonly used in optometric practice.
Visual Disturbance
The importance of visual disturbance in dry eye is underrated. There are few methodologies to assess visual disturbance and visual function in dry eye beyond the black-on-white visual acuity and contrast sensitivity, but the concept deserves discussion here. In the future, methodology capable of quantifying visual disturbance and tear film quality in real time will aid in both diagnosis and management. Until then, a brief description of existing technology follows.
Computer-Vision Symptom Scale
The Computer-Vision Symptom Scale (CVSS17) is a Rasch-based linear scale that explores 15 different symptoms of computer-related visual and ocular symptoms. With the 17 questions, the CVSS17 includes a broad range of symptoms such as photophobia and “blinking a lot.” This has been reported to be valuable in evaluating the computer-related visual and ocular symptoms. Assessing difficulty with prolonged digital screen use, informally or via survey, is increasingly important as the world expands with digital technology. Currently no validated computer use survey for DED exists, although clinicians often collect this information through office surveys or during case history.
Functional Tests of Vision
Functional visual acuity (FVA) is a standardized test for daily activities. It corresponds to the visual acuity measured with the patient’s habitual prescription. The visual maintenance ratio is the average FVA divided by the baseline visual acuity. In patients with DED, Sjögren’s syndrome, and Stevens Johnson syndrome, the FVA is reduced due to irregularity of the ocular surface and induced higher-order aberrations (HOAs). This technology is not widely available yet the concept is conducive to future development in dry eye diagnosis.
Tear Film Stability
Tear film stability is a fundamental in the maintenance of tear film homeostasis, and is a critical diagnostic criterion in DED. Some DED diagnostic algorithms are focused around the assessment of tear film stability and other tear film parameters. Tear film stability can be affected by temperature, humidity, and air circulation, even the use of fluorescein in the assessment of tear film stability can impact the tear film. Tear film stability has been included in the definition of DED by TFOS DEWS II, is considered a core mechanism in dry eye, and is critical in maintaining a smooth refractive surface, thus consistent clear vision. There are many techniques to evaluate the stability of the tear film, including invasive and noninvasive methods, which are described below.
Tear Film Break-Up Time
Tear break-up time (TBUT) is one of the most common methods of assessing tear film stability. The time required for the tear film to break up following a blink is called TBUT. It is a quantitative test for measurement of tear film stability. The normal time for tear film break-up is 15–20 s, and abnormal values are generally accepted to be < 10 s using both invasive (with the instillation of fluorescein) and noninvasive techniques. TBUT measured with the addition of fluorescein to the tear film is often described as fluorescein tear break-up time (FTBUT), while when measured noninvasively using a keratography or similar equipment, it is called noninvasive break-up time (NIBUT). It uses a grid or other patterns directed on the precorneal tear film for observation of image distortion and the time from opening the eyes to the first sign of image distortion is measured in seconds.
Fluorescein Break-Up Time
To perform the test, a fluorescein strip is moistened with saline and applied to the inferior cul-de-sac. After several blinks, the tear film is examined using a broad-beam of slit lamp with a cobalt blue filter for the appearance of the first dry (black) spots on the cornea. TBUT values of less than 5–10 s indicate tear instability and are observed in patients with mild to moderate DED. The FTBUT is a very common and simple diagnostic test used in clinical practice to assess DED. Sodium fluorescein enhances tear film visibility. However, it is said fluorescein reduces the stability of the tear film, therefore care should be taken to follow the same protocol for fluorescein instillation, directions, and filters.
Methods of instilling fluorescein include micropipette or impregnated strips. To avoid ocular surface damage, it should be instilled at the inferior or outer canthus with the excess saline on the strip shaken off first. It is important to instruct the patient to blink naturally three times and then stop blinking and hold the eye open until instructed. Viewing should take place within about 1 minute after instillation for the best result, although some argue the best viewing occurs several minutes after instillation with a yellow wratten filter. It has been reported that patients with mild and moderate DED have a wide range of FBUT values. Since this method involves subjective observation, there have been numerous attempts to automate the procedure in taking the measurements. Also, the instillation of fluorescein should follow after osmolarity or other tear sampling diagnostic tests due to its invasive nature.
Noninvasive Tear Break-Up Time
The principles of noninvasive tear film assessment is to measure tear dynamics over time, using video recording to capture a series of images with the videokeratoscope. Modern digital videokeratoscopes allow the clinician to use a Placido disc image to assess the tear film surface. Automated noninvasive methods are preferred for the evaluation of break-up time and tear film surface quality (TFSQ), since invasive procedures involving fluorescein may destabilize the tear film. High-Speed Videokeratoscopy (Medmont International Pty Ltd., Victoria, Australia) can be used to assess the dynamics of the TFSQ. The reflected image indicates the quality of the tear film surface over time. A uniform pattern is observed on a healthy, regular tear film, whereas an irregular pattern is seen when there is tear film thinning and/or break up. Additionally, NIBUT is also measured with a Keratograph (Oculus K5M, Wetzlar, Germany), which can identify localized breaks and disturbances in the Placido disk pattern, projected in infrared, related to changes in TFSQ. Corneal topographers utilizing placido ring images can also be used, although the measurements are not automated.
Interferometry
Oily substances spread to form a thin layer on the surface of water. Exposure of such an oily layer to adequate light results in the generation of an interferometric fringe pattern from interference from the front and back surface refractive index change reflections. Interferometry can allow the thickness of the lipid layer of the tear film to be estimated. Using slit lamp photometry to measure reflectivity (Tearscope; Keeler, Windsor, UK) that uses broadband illumination to visualize the kinetics of the lipid layer of the tear film, showing that different patterns of interferometric fringe are generated according to the lipid layer thickness. The DR-1 system (Kowa, Nagoya, Japan) was also developed as an interferometer for evaluation of the kinetics of the lipid layer of the tear film in both normal subjects and patients with DED. This system has revealed that lipid layer kinetics is related to the tear film condition or blink pattern. Interferometry is now an established technique for clinical examination that allows visualization of the kinetics of the oily layer of the tear film. The TearScience LipiView interferometer (J&J Vision, Jacksonville, FL) and the lateral shearing interferometer have recently been introduced as the first clinically available instruments to allow automated measurements of the thickness of the lipid layer of the tear film. These instruments are expected to provide new understandings into the lipid layer of the tear film and the pathophysiology of dry eye.
Tear Evaporation Rate
A healthy lipid layer is necessary to prevent tear film evaporation as the evaporation rate indicates the level of tear film stability. Evaporation of the tear film can be measured using different techniques such as a vapor pressure gradient and the velocity of relative humidity increase (resistance hygrometry) within a goggle cup placed over the eye. These techniques have shown that reduced tear film stability (poor lipid layer) has been associated with high evaporation rate and DED symptoms. The evaporation rate is temperature and humidity dependent as well as the time of day being a factor. The rate can also be affected by evaporation from the skin surrounding the eye, and the amount of time between blinks, which is reduced with attentive visual behavior, including screen time. Infrared thermography has been used noninvasively, yet despite these advances, a validated diagnostic measuring technique is yet to be established but would show promise.
Tear Volume and Tear Measurements
An adequate tear film volume is an important factor for ocular surface health. The occurrence of aqueous deficiency and the resultant loss of homeostasis can be a sign of pathogenic mechanism that is observed in a DED patient although it is not stated in the definition of DED directly. Clinically tear volume can be measured with the Schirmer or phenol red thread (PRT) test, or measurement of the tear meniscus as a surrogate measure for aqueous production.
Osmolarity
Osmolarity of normal eye is generally accepted to be < 308mOsm/L, with values between 308 and 316 mOsm/L, an indicator of mild dry eye in the presence of symptoms and/or a differential of >8 mOsm/L between the eyes. Values increase with severity of DED. Osmolarity gives qualitative information of the status of the tear film, using instruments such as the TearLab Osmolarity System (TearLab Corp, San Diego, CA), which was the first commercially available point-of-care diagnostic for dry eye. The TFOS DEWS II diagnostic algorithm recommends osmolarity measurements as a screening test for dry eye. There are a number of diagnostic hand-held or small instruments available or in development/testing to assess osmolarity alone or in combination with other tear film biomarkers. Instruments of this type are attractive for their ease of use, portability, and quantitative assessment.
Meniscometry (Tear Meniscus Assessment)
Meniscometry assesses the tear meniscus height and cross-sectional volume of the tears. It is perhaps the easiest and most common method to assess tear volume quantitatively. In clinical practice practitioners use slit lamp techniques to study tear meniscus height (TMH), and in some cases curvature (TMR), and cross-sectional area (TMA). These measurements have shown comparable results with other DED tests of aqueous production. The TFOS DEWS II diagnostic report suggests that TMH be used as a measure of aqueous deficiency to further subtype dry eye, TMH <0.2 mm considered mild, and <0.1 mm moderate to severe aqueous deficiency. The DED diagnostic suite in the Oculus Keratograph 5M (Wetzlar, Germany) includes automated TMH measurement. While not all practices will have this instrumentation, all eyecare practices have a slit lamp, and can measure TMH as a surrogate measure of aqueous production. Other meniscometry measures, such as optical coherence tomography meniscometry, are available, yet the analysis of the images may be difficult, time consuming, and practitioner-dependent. Hand-held instrumentation is not yet available.
The Phenol Red Thread Test
This test consists of a thin cotton thread soaked in a pH-sensitive dye know as phenol red, placed over the lower lid margin, and is used to measure tear volume when moistened with tears. The PRT and the Schirmer test are highly correlated, yet poorly reproducible, except at lower values. However, assessing tear volume is important in DED and PRT is a rapid test (15 s per eye) and a wetting length of ≤5 mm is considered indicative of moderate dry eye.
The Schirmer Test
The Schirmer test, first described in 1903, quantitatively measures the tear production by the lacrimal gland during fixed time period. The test is performed by placing a thin strip of filter paper in the inferior cul-de-sac over the lid margin. The patient’s eyes are closed for 5 min and the amount of tears that wets the paper is measured in terms of length of wet strip and the value of value of less than 5 mm of strip wetting in 5 min is accepted as diagnostic marker for aqueous tear deficiency, and Sjögren’s syndrome–related dry eye.
Damage to Ocular Surface
Assessment of ocular surface health is a mainstay in DED diagnostic testing. The most common testing is the evaluation of ocular surface damage using vital dyes—fluorescein and lissamine green staining, both of which are readily available in clinical practice. The TFOS DEWS II Diagnostic algorithm recommends the following staining patterns as indicative of a positive DED screening: >5 corneal fluorescein spots, >9 conjunctival lissamine green spots, or lid wiper epitheliopathy (LWE) of the lid margin, ≥2 mm length, ≥25% width. Each is described below.
Ocular Surface Staining
Ocular surface staining includes the cornea and conjunctiva and the most common staining is punctate staining, which can be seen in various ocular surface diseases. Dyes are instilled to the eye surface to assess the quality of tear film, and to diagnose the severity of DED and its management. Sodium fluorescein, rose bengal, and lissamine green are the most common used dyes to assess the integrity of the ocular surface. Rose bengal has cytotoxicity properties and therefore the least preferred dye. Lissamine green has replaced the use of rose Bengal in assessing ocular surfaces. Therefore, lissamine green and fluorescein is used widely in clinical practice as they are equally tolerated. Fluorescein stains the cornea more than the conjunctiva and pools in epithelial erosions, degenerating and dead cells, whereas rose Bengal and lissamine green stain the dead cells and weaken the healthy cells with insufficient protection of the cells. Observing staining of the cornea and conjunctiva between 1 and 4 min post instillation in clinical practice is considered to be a routine part for dry eye assessment as it is a simple and easy procedure to determine the severity of dry eye.
Impression Cytology
Impression cytology is used in the diagnosis of the ocular surface disorders, primarily from a clinical research perspective, and it is a relatively easy and simple technique. Conditions such as limbal stem-cell deficiency, DED, and ocular surface neoplasia can be diagnosed with impression cytology. The most common method using impression cytology is the Nelson classification system, which considers the ratio of conjunctival epithelial and goblet cells in terms of their density, morphology, cytoplasmic staining affinity, and nucleus/cytoplasm. Clinical devices such as the Eyeprim device (OPIA Technologies, Paris, France) can be used to standardize the area and pressure used in collecting the sample for further analysis (see ocular surface inflammation, below).
Lid-Parallel Conjunctival Folds
Lid-parallel conjunctival folds (LIPCOF) are folds in the adjacent, lower quadrant of the bulbar conjunctiva, parallel to the lower lid margin. LIPCOF may be the first sign of mild stages of conjunctivochalasis and, therefore, encounter the same etiology, but clinically they show slightly different characteristics. Patients with increased LIPCOF severity are likely to suffer from DED. The combination of nasal LIPCOF and NIBUT has been shown to be the most predictive DED test combination, and LIPCOF should not be overlooked, especially DED that is nonresponsive to treatment.
In Vivo Confocal Imaging
In vivo confocal microscopy (IVCM) is a noninvasive technique that allows the evaluation of signs of ocular surface damage in DED at a cellular level, including decreased corneal and conjunctival epithelial cell density, conjunctival squamous metaplasia, decreased corneal nerve density, and increased tortuosity. Laser scanning IVCM allows easy identification of conjunctival goblet cells suggesting it may be a valuable tool in assessing and monitoring DED-related ocular surface damage. The IVCM has not been widely adopted in clinical practice but is used in clinical research settings, although it is a less invasive technique and has shown to be more effective than impression cytology.
Ocular Surface Sensitivity
With the increased focus on neurosensory and pain disorder aspects of dry eye, assessment of ocular surface sensitivity has become more commonplace. It has been documented that loss of corneal sensitivity can give rise to significant corneal disorders such as neurotrophic keratopathy. Cochet–Bonnet or noncontact air-jet esthesiometry can be useful tests to evaluate corneal sensation. In addition, the cotton wisp test can be easily performed in the clinic and should be considered if signs and symptoms are disproportionate to one another.
Inflammation of the Ocular Surface
Inflammation is a recognized component of the pathophysiological mechanism of DED and has been shown to be a stable indicator of severity. Clinically, ocular surface injection can be an indicator of inflammation, yet this can be a challenge to assess because baseline injection is rarely established via description in the record or with photography. Assessment of tear film inflammatory markers is common in a lab-based clinical research setting, and to a lesser degree in the clinical office based on available point-of-care technology. This direction, though having point-of-care diagnostics for inflammatory or other biomarkers in the tear film, and a paired treatment that results in measurable change in the diagnostic biomarker, is the future direction of quantitative ocular surface diagnostics. Reproducible and noncost limiting lab-on-chip technology will be the future of DED diagnosis and management.
Clinicians need to be mindful that the ocular inflammation tests are not explicit for DED. For those patients where the history-taking for differential diagnosis suggests that this might not be primary DED, a full differential diagnosis should be performed using a slit lamp biomicroscope to examine the eyelashes for signs of swelling, blepharitis, demodex folliculorum, meibomian gland dysfunction (MGD), and assessing cornea for ulceration. It can be helpful to have published diagnostic score criteria to screen patients who may need further testing or patients free of symptoms, but show an anomalous sign indicative of dry eye and similar diagnoses. It is also helpful if the tests can be readily performed without too many difficulties on technical aspects or time, and some of the tests may be problematic when used in a population without normal reference values. Presently most practitioners do not routinely include any tests for inflammation as an initial screening requirement for clinical diagnosis of DED. However, in practices that focus on ocular surface disease as a specialization, it is reasonable to expect evaluation of the inflammatory status of the ocular surface.
Ocular/Conjunctival Redness (Injection)
Conjunctival redness occurs when conjunctival vessels are dilated, both the fine vasculature and/or larger diameter vessels. Conjunctival injection is likely the most common clinical sign of ocular surface inflammation. A penlight (torch) or standard slit lamp biomicroscopic examination can easily detect the condition. Recently more quantitative documentation methods have been developed using digital imaging analysis for diagnosis and treatment purposes. At least one instrument, the Oculus Keratograph 5M (Wetzlar, Germany) provides a “redness score” that can be used to compare eyes or visit-to-visit changes. Injection of the lid margin can also be assessed photographically for changes between visits and is often evaluated in context with LWE and/or MGD when DED is suspected.
Matrix Metalloproteinase-9
Dry eye is often accompanied by increased osmolarity of the tear film and inflammation of the ocular surface. Hyperosmolarity contributes to the inflammatory cascade, leading to epithelial cell distress and upregulation of inflammatory processes. Increased cytokines and matrix metalloproteinase-9 (MMP-9) levels have been demonstrated in DED. The MMP-9 diagnostic test can detect enzyme activity levels using an in-office rapid assay. The current diagnostic device (InflammaDry, Rapid Pathogen Screening, Inc, Sarasota, FL, USA) can examine tear MMP-9 levels in 10 minutes. This semiquantitative test provides a positive mark (pink line) if the MMP-9 levels are >42 pg/mL. Some practitioners use this test as a screening tool, while most use the test when an inflammatory dry eye is strongly suspected.
Ocular Surface Immune Markers including Cytokines and Chemokines
The levels of tear cytokines and chemokines are important and reflect the level of epithelial disease. Since collection of tear fluid is relatively noninvasive compared to biopsies or venipuncture for serum assays, it is an attractive idea to include these as diagnostic tools, and several are in development.
In each of these pending diagnostics, tear fluid is collected using a pen-like instrument or glass microcapillary tubes. Glass microcapillary tubes of small volume, typically 0.5–5 μL, are placed in the inferior and temporal tear prism, and capillary action draws the tears into the tube. The tears can be frozen for analysis or expelled onto an appropriate substrate (or into a diagnostic instrument) for analysis. Pen-like devices, similar to the TearLab osmolarity instrument (TearLab Corp, San Diego, CA), can also be platforms for tear collection and analysis. In general, the tip of the device is disposable, and the reaction and/or measurement occurs in or on the surface of the tip.
Impression cytology, described above, is a method for collection of surface cells and is used to collect samples for immune markers. A Class-II MHC antigen, HLA-DR, is the most commonly used ocular surface immune marker and indicates a loss of the normally immune suppressed environment of the ocular surface. The commercially available Eyeprim membrane (Opia Technology, Paris, France) has shown to be a suitable impression membrane to harvest conjunctival epithelial cells for the quantification of HLA-DR. It has been shown that not all DED cases are equally inflammatory, and other non-DED causes of ocular surface inflammation can be reflected by this nonspecific inflammatory marker.
Eyelid Evaluation
Evaluation of the eyelids and eyelashes is a routine component of the ocular examination. Anterior eyelid conditions, such as anterior blepharitis and demodex blepharitis, are differential diagnoses and comorbidities of DED and should be ruled out in making a diagnosis of DED. Evaluation of posterior eyelid conditions, including MGD, is a critical part of the dry eye examination.
Blink/Lid Closure Analysis
Blinking is essential in maintaining optical performance, the health of the ocular surface, and meibum distribution, which helps reforming a proper tear film lipid layer. Incomplete blinking can result in DED symptoms, exposure keratopathy, and corneal staining. Incomplete blinks can be observed using fluorescein and the pattern is visible as a dark line indicating the movement limit of the upper eyelid due to previous incomplete blink. Complete blink count can be measured in conjunction with tear film/lipid layer interferometry using the TearScience Lipiview (J&J Vision, Jacksonville, FL). The blink can be observed in real time and also via video.
Lid Wiper Epitheliopathy
A small portion of the marginal conjunctiva of the upper and lower lid acts as a wiping surface to spread the tear film over the ocular surface. This contacting surface at the lid margin has been termed the “lid wiper.” LWE is a term that describes an insult to the lid wiper epithelia accompanied by subclinical inflammation. This condition is believed to be caused by increased friction between this region and the ocular surface due to poor lubrication and it has been found that dry eye patients suffer from this condition. LWE cannot be identified using white light, therefore, staining techniques using lissamine green and fluorescein need to be applied. LWE can be observed immediately adjacent to the lid margin of the everted eyelid using a slit lamp biomicroscope and is most commonly classified by combining the extent of its staining, in terms of length in mm, and width relative to the lid margin width. Evaluation and identification of presence or absence of LWE and ocular surface inflammation with tear osmolarity measurements can help to correctly diagnose DED.
Meibometry, Meibography, and Meiboscopy
Meibomian glands are sebaceous glands that can be found in the upper and lower lids. There are approximately 30 meibomian glands in the upper lid and 25 in the lower lid. When meibomian gland ductal epithelium or posterior lid margin tissues undergo keratinization, possibly due to increased osmolarity or low-grade chronic inflammation, alterations in meibomian gland secretions, called meibum, meibomian gland obstruction can occur. MGD is thought to be reflected by quantity, quality, and expressibility of the glands, which can be determined by the application of digital pressure to the glands and evaluation of the meibum expression. Normal meibum is clear and readily expressed with gentle pressure in the normal and healthy eyelid. In contrast, it becomes cloudy and then opaque, losing its viscosity and becoming toothpaste-like, not too easy to express in patients with severe MGD. Gland expression can be done digitally, with cotton tip applicators or with one of a number of small hand-held devices. The most common clinical expression grading scheme is a 0–4 scale, where grade 0 is normal, clear expression, grade 1 is slightly cloudy meibum, grade 2 is cloudy to opaque meibum, grade 3 is opaque “toothpaste sign,” and grade 4 is no expression. This is a “summed” gestalt grade across the lid margin. Some clinicians grade expression by the worst grade seen across the lid, and other reports grade each gland within the central eight glands. There is not a validated and widely accepted clinical grading scheme, which is also noted in the TFOS DEWS II diagnostic algorithm, where MGD is graded as “mild, moderate, and severe” without further description. Consistency in technique with good chart notation or photography aids in comparison across visits or with treatment.
It has been suggested that MGD may be the leading cause of DED throughout the world. In recent decades innovations in ocular imaging have advanced significantly to develop techniques, technologies, and methods of image analysis and test for diagnosing MGD. These diagnostic techniques include methods such as meibometry, meibography, and meiboscopy, meibography being the most frequently performed. Meibometry is a simple test for quantifying the amount of lipid at the lid margin. Meibography allows observation of the silhouette of the meibomian gland morphological structure by using photo or video documentation. Meiboscopy is similar to meibography, and requires a slit lamp and transilluminator without expensive instrumentation.
Recent advances in technology have led to the development of a noncontact, stand-alone, or slit lamp mounted meibography systems. Several different scoring scales, such as the meiboscore, have been proposed for the evaluation of meibography. Meibography has been also used to visualize and evaluate meibomian gland area quantitatively using software that is currently under development, and several studies are underway to validate these quantitative programs. However, other clinical parameters should be considered as meibography alone does not appear to be sufficient when diagnosing MGD. Several instruments can measure more than one tear film parameter, such as lipid layer thickness measured by interferometry (TearScience LipiView, J&J Vision, Jacksonville, FL) and the addition of an instrument that has multiple diagnostic abilities, such as meibography, NIBUT, photography, videography, a meniscus measurement, and lipid layer thickness can be an asset to growing the dry eye practice.
DED Diagnostic Test Batteries and Test Order
Unfortunately, there is no single diagnostic test to definitively diagnose DED, and the results of diagnostic tests discussed above do not always correlate with symptoms. Symptoms remain a very important diagnostic test in DED and it is critical to revisit symptomology in the presence of ocular signs, as patients can inadvertently neglect reporting symptoms without a prompt. In addition to symptoms, tear film stability measured by break-up time, corneal integrity assessment via vital dye staining, and osmolality remain the three recommended screening tests. The TFOS DEWS II diagnostic report suggests any one abnormal result, in the presence of symptoms, is adequate for a dry eye diagnosis, and that a diagnosis can be made without expensive instrumentation, as well as in the context of a routine examination. Following a positive dry eye screening, further assessment of aqueous production and MGD help further classify the dry eye subtype and provide direction for treatment. Unfortunately there isn’t a single qualitative/quantitative test that is capable of assessing severity of the disease, or response to treatment, but the future is bright with a number of point-of-care in-office diagnostic platforms to measure biomarkers—inflammatory and other. Until that time though, dry eye diagnosis does not have to be difficult. Keep it simple, ask symptom questions, screen for dry eye, exclude conditions that can mimic DED, further classify dry eye as MGD or aqueous deficient (or some amount of both), initiate management, and follow-up. Keeping up with new ocular surface diagnostic technologies can aid in building and growing the dry eye practice of the future.
Reference
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